Effect of phosphatidylinositol-3 kinase inhibition on ovotoxicity caused by 4-vinylcyclohexene diepoxide and 7, 12-dimethylbenz[a]anthracene in neonatal rat ovaries.
Effect of phosphatidylinositol-3 kinase inhibition on ovotoxicity caused by 4-vinylcyclohexene diepoxide and 7, 12-dimethylbenz[a]anthracene in neonatal rat ovaries.
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DOI：
10.1016/j.taap.2009.08.012
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发表时间：
2009-12-01
影响因子：
3.8
通讯作者：
Hoyer PB
中科院分区：
文献类型：
--
作者：
Keating AF;J Mark C;Sen N;Sipes IG;Hoyer PB
4-乙烯基环己烯二环氧化物（VCD）是一种特异性破坏小鼠和大鼠卵巢中的原始卵泡和小初级卵泡的促排卵剂。相比之下，7，12-二甲基苯并[a]蒽（DMBA）对所有卵泡类型都有卵毒性。本研究调查了磷脂酰肌醇-3激酶信号参与VCD和DMBA诱导的卵毒性。将出生后（PND）4天Fischer 344（F344）大鼠全卵巢在溶剂对照、VCD（30 μM）或DMBA（1 μM）、± PI 3激酶抑制剂LY 294002（20 μM）或其无活性类似物LY 303511（20 μM）中培养2- 12天。培养后，对卵巢进行组织学评价，并对健康卵泡进行分类和计数。PI 3激酶抑制对原始卵泡数量没有影响，但从第4天开始减少（P < 0.05）小初级卵泡和大卵泡。VCD从第6天开始引起原始卵泡和小初级卵泡的丢失（P < 0.05）。在抑制PI 3激酶的情况下，VCD对原始卵泡无明显影响（P > 0.05），但引起小初级卵泡丢失（P < 0.05）。DMBA染毒组第6天原始卵泡和小初级卵泡丢失（P < 0.05）。此外，DMBA诱导的原始卵泡和小初级卵泡损失在PI 3激酶抑制下比单独使用DMBA更大（P < 0.05）。这些结果支持1）PI 3激酶介导原始卵泡到小初级卵泡的募集，2）VCD（而不是DMBA）通过增加原始卵泡到小初级卵泡的募集来增强卵毒性，3）除了外源性诱导的卵毒性外，VCD也是一种有用的模型化学品，用于阐明参与原始卵泡募集的信号传导机制。
4-vinylcyclohexene diepoxide (VCD) is an ovotoxicant that specifically destroys primordial and small primary follicles in the ovaries of mice and rats. In contrast, 7,12-dimethylbenz[a]anthracene (DMBA) is ovotoxic to all ovarian follicle classes. This study investigated phosphatidylinositol-3 kinase signaling involvement in VCD- and DMBA-induced ovotoxicity. Postnatal day (PND) 4 Fischer 344 (F344) rat whole ovaries were cultured for 2–12d in vehicle control, VCD (30 μM), or DMBA (1 μM), ± PI3 kinase inhibitor LY294002 (20 μM) or its inactive analog LY303511 (20 μM). Following culture, ovaries were histologically evaluated, and healthy follicles were classified and counted. PI3 kinase inhibition had no effect on primordial follicle number, but reduced (P < 0.05) small primary and larger follicles beginning on d4. VCD caused primordial and small primary follicle loss (P < 0.05) beginning on d6. With PI3 kinase inhibition, VCD did not affect primordial follicles (P > 0.05) at any time, but did cause loss (P < 0.05) of small primary follicles. DMBA exposure caused primordial and small primary follicle loss (P < 0.05) on d6. Further, DMBA-induced primordial and small primary follicle loss was greater with PI3 kinase inhibition (P < 0.05) than with DMBA alone. These results support that 1) PI3 kinase mediates primordial to small primary follicle recruitment, 2) VCD, but not DMBA, enhances ovotoxicity by increasing primordial to small primary follicle recruitment, and 3) in addition to xenobiotic-induced ovotoxicity, VCD is also a useful model chemical with which to elucidate signaling mechanisms involved in primordial follicle recruitment.
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